Nordihydroguaiaretic Acid (NDGA) is a polyphenol, antioxidant, natural product lignan isolated from the creosote bush (Larrea tridentata). The in vivo and in vitro Pharmacology and Toxicology of NDGA has been continuously studied for more than 36 years. The Pharmacology of NDGA has been studied in Diabetes, Alzheimer's disease and Amyotrophic Sclerosis. Most of the research on NDGA has been in anticancer and cancer prevention models. Toxicology studies reveal NDGA-mediated hepatotoxicity and nephrotoxicity. This data has influenced a recent interest in semi-synthetic derivatives of NDGA focused on modifying the phenolic groups which are responsible for in vivo toxicity. The tetra-methylether of NDGA (M4N) has shown reduction in toxicity and enhanced anti-melanoma activity when compared to NDGA.The specific aim of this project was to increase the number of NDGA analogs with anti-melanoma activity and explore a novel synthetic approach by binding the ortho-phenols together by one atom, creating a 5-membered ring as opposed to the prior work which involved tetra-substituted phenolic hydroxyl group modifications.Eleven new analogs were synthesized, characterized and evaluated for their anti-melanoma activity. The anti-melanoma activity was evaluated by 5-day colorimetric-based, and DNA, RNA and protein synthesis inhibition-based cytotoxicity assays. The cytotoxicity assays were compared to NDGA and M4N in terms of structure and activity. Selected analogs were evaluated in an in vivo, mouse, tumor growth inhibition model. In the first in vivo model, tetra acetyl NDGA (TA-NDGA) and ortho-cyclic carbonate NDGA (OCC-NDGA) were evaluated at two dose-levels, 100 mg/kg and 200 mg/kg. They both showed dose-dependent, but moderate tumor growth inhibition at the 200 mg/kg dose-level. An ortho-cyclic sulfate of NDGA showed in vivo toxicity at 100 mg/kg. In the second in vivo model, the dose was escalated to 300 mg/kg, TA-NDGA showed moderate tumor growth inhibition, but OCC-NDGA-mediated tumor growth inhibition was not repeated. However, in the second study an ortho-difluoromethylene NDGA analog did show moderate tumor growth inhibition.Structure-activity relationships indicated that the ortho-cyclic analogs are inferior to the tetra-substituted phenolic group-modified analogs in terms of anti-melanoma activity and therefore future synthesis' should be focused on generating more tetra-substituted phenolic group analogs of NDGA.

Nordihydroguaiaretic Acid (NDGA) is a polyphenol, antioxidant, natural product lignan isolated from the creosote bush (Larrea tridentata). The in vivo and in vitro Pharmacology and Toxicology of NDGA has been continuously studied for more than 36 years. The Pharmacology of NDGA has been studied in Diabetes, Alzheimer's disease and Amyotrophic Sclerosis. Most of the research on NDGA has been in anticancer and cancer prevention models. Toxicology studies reveal NDGA-mediated hepatotoxicity and nephrotoxicity. This data has influenced a recent interest in semi-synthetic derivatives of NDGA focused on modifying the phenolic groups which are responsible for in vivo toxicity. The tetra-methylether of NDGA (M4N) has shown reduction in toxicity and enhanced anti-melanoma activity when compared to NDGA.The specific aim of this project was to increase the number of NDGA analogs with anti-melanoma activity and explore a novel synthetic approach by binding the ortho-phenols together by one atom, creating a 5-membered ring as opposed to the prior work which involved tetra-substituted phenolic hydroxyl group modifications.Eleven new analogs were synthesized, characterized and evaluated for their anti-melanoma activity. The anti-melanoma activity was evaluated by 5-day colorimetric-based, and DNA, RNA and protein synthesis inhibition-based cytotoxicity assays. The cytotoxicity assays were compared to NDGA and M4N in terms of structure and activity. Selected analogs were evaluated in an in vivo, mouse, tumor growth inhibition model. In the first in vivo model, tetra acetyl NDGA (TA-NDGA) and ortho-cyclic carbonate NDGA (OCC-NDGA) were evaluated at two dose-levels, 100 mg/kg and 200 mg/kg. They both showed dose-dependent, but moderate tumor growth inhibition at the 200 mg/kg dose-level. An ortho-cyclic sulfate of NDGA showed in vivo toxicity at 100 mg/kg. In the second in vivo model, the dose was escalated to 300 mg/kg, TA-NDGA showed moderate tumor growth inhibition, but OCC-NDGA-mediated tumor growth inhibition was not repeated. However, in the second study an ortho-difluoromethylene NDGA analog did show moderate tumor growth inhibition.Structure-activity relationships indicated that the ortho-cyclic analogs are inferior to the tetra-substituted phenolic group-modified analogs in terms of anti-melanoma activity and therefore future synthesis' should be focused on generating more tetra-substituted phenolic group analogs of NDGA.

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dc.type

text

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dc.type

Electronic Dissertation

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dc.subject

Nordihydroguaiaretic acid

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dc.subject

Medicinal Chemistry

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dc.subject

Synthesis

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dc.subject

Cancer

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dc.subject

Melanoma

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thesis.degree.name

Ph.D.

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thesis.degree.level

doctoral

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thesis.degree.discipline

Nutritional Sciences

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thesis.degree.discipline

Graduate College

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thesis.degree.grantor

University of Arizona

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dc.contributor.advisor

Alberts, David S.

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dc.contributor.advisor

Dorr, Robert T.

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dc.contributor.chair

Alberts, David S.

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dc.contributor.committeemember

Dorr, Robert T.

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dc.contributor.committeemember

Romagnolo, Donato

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dc.contributor.committeemember

Gunatilaka, Leslie

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dc.contributor.committeemember

Remers, William

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dc.identifier.proquest

1086

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dc.identifier.oclc

137353908

en_US

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